(1) We analyzed our 4-year case-control study of severe malaria in Pursat, Cambodia, and found that increasing age (but not hemoglobin E) confers protection against severe disease. (2) We measured parasite clearance rates in response to artesunate in patients with uncomplicated malaria in Pursat, Preah Vihear and Ratanakiri and have found that artemisinin resistance is entrenched, emerging and uncommon in these three provinces, respectively. (3) We associated prolonged parasite clearance rates in Cambodia and elsewhere in Southeast Asia with various mutations in K13, a kelch protein expressed by P. falciparum. (4) Through whole-genome sequence analysis, we identified subpopulations of artemisinin-resistant P. falciparum parasites in Pursat and Preah Vihear, Cambodia, and discovered four mutations that constitute a genetic background on which K13 mutations arise and confer artemisinin resistance. (5) Using genetically-edited parasites, we confirmed that K13 mutations are causal for artemsinin resistance in vitro. (6) We developed and validated an ex vivo assay to detect artemisinin-resistant parasites in the field and an in vitro assay to investigate the molecular mechanism of artemisinin resistance in the laboratory. (7) We completed a study showing that chloroquine remains highly effective for the treatment of P. vivax malaria in Pursat, Cambodia. (8) We completed a study of the efficacy of dihydroartemisinin-piperaquine in the treatment of uncomplicated P. falciparum malaria in Pursat, Preah Vihear and Ratanakiri provinces in Cambodia.